Combining Conventional and Biologic Therapies

Combining Conventional and Biologic Therapies

BARCELONAClinical and scientific rationale increasingly
supports the use of cytotoxic and bio-logic agents in combination to
treat breast cancer, a Spanish oncologist asserted during a satellite
meeting at the San Antonio Breast Cancer Symposium, sponsored by
Bristol-Myers Squibb Oncology.

I think it is clear that the combination of conventional agents
with biologics is more than a promising approach, said Jose
Baselga, MD, chairman of oncology, Vall dHebron General
Hospital, Barcelona. In particular, Herceptin [trastuzumab]
given with chemotherapy does enhance clinical benefit in patients who
have HER-2-expressing tumors.

There is also a rationale for combining biologic agents and then
adding those combinations to chemotherapy, he said.

We are facing a very interesting situation in which we will
have to do studies to prove that the new combinations are of use and
that biologic agents are of use in earlier disease. A whole series of
adjuvant trials is planned.

Dr. Baselga is among investigators worldwide who are evaluating a
wide range of new biologic compounds, such as inhibitors of epidermal
growth factor receptor (EGFR) and tyrosine kinase.

Tyrosine kinase inhibitors are very small molecules, he
said. We have found we can prevent receptor phosphorylation
completely with small doses of the inhibitor. There appears to be a
relationship between the number of receptors and sensitivity to the
compound in breast cancer models.

Arguably, the synergy between biologic and cytotoxic agents has been
demonstrated most clearly with paclitaxel (Taxol) and Herceptin (see
box for a possible explanation of this synergism).

Possible Mechanism of Herceptin/Taxol Synergy

Recent laboratory investigations have provided insight into the means
by which trastuzumab (Herceptin) and paclitaxel (Taxol) might have
synergy. In particular, the evidence suggests that effects on cell
cycle proteins might account for the increased antitumor activ-ity
seen with the combination, Dr. Jose Baselga said in his San Antonio presentation.

Paclitaxel activates p34, which plays a role in regulating apoptosis.
Overexpression of HER-2 is associated with activation of p21, which
appears to interact with p34 in ways that inhibit paclitaxels
antitumor activity.

If this, in fact, is what is happening, it would be a good idea
to use a compound that decreases the amount of HER-2 in cells, and
that is what happens with Herceptin, he said.

In a series of preclinical studies, Dr. Baselga and his colleagues
evaluated single-agent treatment with Herceptin, doxorubicin, or
paclitaxel. They then combined each chemotherapeutic agent with Herceptin.

Enhanced Antitumor Response

Combining Herceptin with either chemotherapeutic agent resulted in
enhanced antitumor response, compared to treatment with individual
agents. However, the greatest inhibitory effect occurred when
paclitaxel and Herceptin were combined (Cancer Research 58:2825-2831,
1998).

The combination of Taxol and Herceptin resulted in complete
elimination of tumors in a much higher percentage of cases than with
either agent alone, Dr. Baselga said. The model was
biased against responses because the therapy was not started until
the tumors were of an important size. We observed the effects with
three different dose levels and two different dose schedules of Taxol.

He added that there has been no risk of severe adverse events with
Herceptin used in combination, other than the cardiac risk that
has been observed when Herceptin is given ith anthracyclines. The
cardiac risk is not observed when Herceptin is given with paclitaxel.

Dr. Baselga said a next logical step will be to evaluate biologic
combinations for additive or synergistic effects. Some evidence
already suggests that anti-EGFR antibodies and HER-2 antibodies are
synergistic in combination, he added.

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